The American Myth of Markets in Social Policy: Ideological Roots of Inequality

The American Myth of Markets in Social Policy examines how implementing American tropes in policy design inadvertently frustrates policy goals. It investigates multiple market-oriented designs including funding for private organizations to deliver public services, funding for individuals to buy services, and policies incentivizing or mandating private actors to provide social policy. The author shows that these solutions often not only fail to achieve social goals, but, in fact, actively undermine them, for example saddling the poor with debt or encouraging discrimination. The book carefully details the mechanisms through which this occurs, for example a mismatch between program goals and either contract terms or individual preferences. The author examines several policies in depth, covering universal social insurance programs like healthcare and pensions, as well as smaller interventions like programs for the homeless. The author builds the argument using detailed empirical evidence as well as anecdote, keeping the book accessible and entertaining.

Enhanced Caching Strategies At the Edge of LTE Mobile Networks

With a boom in the usage of mobile devices for traffic-heavy applications, mobile networks struggle to deliver good performance while saving resources to support more users and save on costs. In this paper, we propose enhanced strategies for the preemptive migration of content stored in Information-Centric Networking caches at the edge of LTE mobile networks. With such strategies, the concept of content following the users interested in it becomes a reality and content within caches is more optimized towards the requests of nearby users. Results show that the strategies are feasible, efficient and, when compared to default caching strategies, ensure that content is delivered faster to end users while using bandwidth and storage resources more efficiently at the core of the network.

Trends in Human-Centric Multimedia Networking Scenarios

The evolution of wireless access technologies and mobile devices, together with the constant demand for video services, has created new Human-Centric Multimedia Networking (HCMN) scenarios. However, HCMN poses several challenges for content creators and network providers to deliver multimedia data with an acceptable quality level based on the user experience. Moreover, human experience and context, as well as network information play an important role in adapting and optimizing video dissemination. In this paper, we discuss trends to provide video dissemination with Quality of Experience (QoE) support by integrating HCMN with cloud computing approaches. We identified five trends coming from such integration, namely Participatory Sensor Networks, Mobile Cloud Computing formation, QoE assessment, QoE management, and video or network adaptation.

A novel treatment planning methodology for high dose 166Ho-DOTMP therapy in patients with multiple myeloma

Bone marrow ablation, i.e., the complete sterilization of the active bone marrow, followed by bone marrow transplantation (BMT) is a comment treatment of hematological malignancies. The use of targeted bone-seeking radiopharmaceuticals to selectively deliver radiation to the adjacent bone marrow cavities while sparing normal tissues is a promising technique. Current radiopharmaceutical treatment planning methods do not properly compensate for the patient-specific variable distribution of radioactive material within the skeleton. To improve the current method of internal dosimetry, novel methods for measuring the radiopharmaceutical distribution within the skeleton were developed. 99mTc-MDP was proven as an adequate surrogate for measuring 166Ho-DOTMP skeletal uptake and biodistribution, allowing these measures to be obtained faster, safer, and with higher spatial resolution. This translates directly into better measurements of the radiation dose distribution within the bone marrow. The resulting bone marrow dose-volume histograms allow prediction of the patient disease response where conventional organ scale dosimetry failed. They indicate that complete remission is only achieved when greater than 90% of the bone marrow receives at least 30 Gy. ^ Comprehensive treatment planning requires combining target and non-target organ dosimetry. Organs in the urinary tract were of special concern. The kidney dose is primarily dependent upon the mean transit time of 166 Ho-DOTMP through the kidney. Deconvolution analysis of renograms predicted a mean transit time of 2.6 minutes for 166Ho-DOTMP. The radiation dose to the urinary bladder wall is dependent upon numerous factors including patient hydration and void schedule. For beta-emitting isotopes such as 166Ho, reduction of the bladder wall dose is best accomplished through good patient hydration and ensuring a partially full bladder at the time of injection. Encouraging the patient to void frequently, or catheterizing the patient without irrigation, will not significantly reduce the bladder wall dose. ^ The results from this work will produce the most advanced treatment planning methodology for bone marrow ablation therapy using radioisotopes currently available. Treatments can be tailored specifically for each patient, including the addition of concomitant total body irradiation for patients with unfavorable dose distributions, to deliver a desired patient disease response, while minimizing the dose or toxicity to non-target organs. ^

C4I Roadmap March 2005

Patients expect to be safe from harm inside the walls of a hospital. Increasing reports of medical errors and adverse events have brought these concerns to public attention. Although we have celebrated many scientific advances over the past several decades, many patients do not benefit because the healthcare infrastructure is inadequate to deliver care to all. Studies confirm opportunities to improve in areas such as inpatient vaccination for flu and outpatient screening for breast, cervical or colon cancer. (Institute of Medicine, (IOM), 2000, 2001, 2004). This document outlines the steps needed to further increase our focus on patient safety in John Dempsey Hospital through the development of a multi-disciplinary Collaborative Center for Clinical Care Improvement (CCCCI). The dimensions of safety and outcomes are briefly discussed to provide some perspective on the scope of these challenges (Strongwater, 2003).

Examination of the engraftment of exogenous mesenchymal stem cells in ovarian tumors and their potential use as delivery vehicles for therapeutic genes

Interactions between neoplastic cells and the host stroma play a role in both tumor cell migration and proliferation. Stromal cells provide structural support for malignant cells, modulate the tumor microenvironment, and influence phenotypic behavior as well as the aggressiveness of the malignancy. In response, the tumor provides growth factors, cytokines, and cellular signals that continually initiate new stromal reactions and recruit new cells into the microenvironment to further support tumor growth. Since growing tumors recruit local cells, as well as supplemental cells from the circulation, such as fibroblasts and endothelial precursors, the question arises if it would be possible to access circulating stromal cells to modify the tumor microenvironment for therapeutic benefits. One such cell type, mesenchymal stem cells (MSC), could theoretically be engrafted into stroma. MSC are pluripotent cells that have been shown to form stromal elements such as myofibroblasts, perivascular tissues and connective tissues. Several reports have demonstrated that MSC can incorporate into sites of wound healing and tissue repair, due to active tissue remodeling and local paracrine factors, and given the similarity between wound healing and the carcinoma induced stromal response one can hypothesize that MSC have the potential to be recruited to sites of tumor development. In addition, gene-modified MSC could be used as cellular vehicles to deliver gene products into tumors. My results indicate that MSC home to and participate in tumor stroma formation in ovarian tumor xenografts in mice. Additionally, once homed to tumor beds, MSC proliferate rapidly and integrate. My studies aim at understanding the fate of MSC in the tumor microenvironment, as well as utilizing them for cellular delivery of therapeutic genes into the stroma of ovarian carcinomas. ^

Reduction of setup uncertainties and tumor motion in the radiation therapy of lung tumors

Because the goal of radiation therapy is to deliver a lethal dose to the tumor, accurate information on the location of the tumor needs to be known. Margins are placed around the tumor to account for variations in the daily position of the tumor. If tumor motion and patient setup uncertainties can be reduced, margins that account for such uncertainties in tumor location in can be reduced allowing dose escalation, which in turn could potentially improve survival rates. ^ In the first part of this study, we monitor the location of fiducials implanted in the periphery of lung tumors to determine the extent of non-gated and gated fiducial motion, and to quantify patient setup uncertainties. In the second part we determine where the tumor is when different methods of image-guided patient setup and respiratory gating are employed. In the final part we develop, validate, and implement a technique in which patient setup uncertainties are reduced by aligning patients based upon fiducial locations in projection images. ^ Results from the first part indicate that respiratory gating reduces fiducial motion relative to motion during normal respiration and setup uncertainties when the patients were aligned each day using externally placed skin marks are large. The results from the second part indicate that current margins that account for setup uncertainty and tumor motion result in less than 2% of the tumor outside of the planning target volume (PTV) when the patient is aligned using skin marks. In addition, we found that if respiratory gating is going to be used, it is most effective if used in conjunction with image-guided patient setup. From the third part, we successfully developed, validated, and implemented on a patient a technique for aligning a moving target prior to treatment to reduce the uncertainties in tumor location. ^ In conclusion, setup uncertainties and tumor motion are a significant problem when treating tumors located within the thoracic region. Image-guided patient setup in conjunction with treatment delivery using respiratory gating reduces these uncertainties in tumor locations. In doing so, margins around the tumor used to generate the PTV can be reduced, which may allow for dose escalation to the tumor. ^

Community referral for promoting physical activity among primary care patients

Introduction. There is a need for physical activity interventions based in primary care clinics that take advantage of community resources. The purpose of this randomized controlled trial was to compare the effects of two physical activity interventions: (1) physical activity prescription by a primary care provider plus referral to community physical activity resources and (2) physical activity prescription only. ^ Methods. Sedentary adult patients recruited from a general medicine clinic were randomized to receive a physical activity prescription, delivered by the primary care provider, plus referral to community physical activity resources (n=38) or physical activity prescription only (n=32). Outcomes were use of community resources (exercise facility and personal trainers), physical activity levels (self-report questionnaire and pedometer), and attitudes regarding physical activity assessed at 8 weeks. ^ Results. Three of 38 (7.9%) subjects referred to the community resources and none of the 32 subjects in the prescription only group used the community resources during the 8 week trial. Sixteen of 32 subjects in the prescription plus referral group and 19 of 38 in the prescription group completed the self-report follow-up forms at 8 weeks. For minutes of moderate- or vigorous-intensity physical activity per week, there were no between-group differences at baseline, follow-up, or change from baseline to follow-up. However, for moderate- and vigorous-intensity physical activity, there were significant improvements from baseline to follow-up within each group. For attitudes related to physical activity, there were no between-group differences at baseline, follow-up, or change from baseline to follow-up; neither were there any within-group changes. ^ Discussion. Physical activity prescription delivered by a healthcare provider in the context of a routine primary care visit can improve physical activity levels, with no additional improvement gained by referring to community resources. The intervention was feasible for primary care providers to deliver, but only 50% of subjects returned the self-report physical activity questionnaire at the 8 week assessment. ^

Procedure for the identification of population characteristics for targeting intervention services on the basis of outcome-goal priorities: Case management services for the chronic mentally ill

Although the processes involved in rational patient targeting may be obvious for certain services, for others, both the appropriate sub-populations to receive services and the procedures to be used for their identification may be unclear. This project was designed to address several research questions which arise in the attempt to deliver appropriate services to specific populations. The related difficulties are particularly evident for those interventions about which findings regarding effectiveness are conflicting. When an intervention clearly is not beneficial (or is dangerous) to a large, diverse population, consensus regarding withholding the intervention from dissemination can easily be reached. When findings are ambiguous, however, conclusions may be impossible.^ When characteristics of patients likely to benefit from an intervention are not obvious, and when the intervention is not significantly invasive or dangerous, the strategy proposed herein may be used to identify specific characteristics of sub-populations which may benefit from the intervention. The identification of these populations may be used both in further informing decisions regarding distribution of the intervention and for purposes of planning implementation of the intervention by identifying specific target populations for service delivery.^ This project explores a method for identifying such sub-populations through the use of related datasets generated from clinical trials conducted to test the effectiveness of an intervention. The method is specified in detail and tested using the example intervention of case management for outpatient treatment of populations with chronic mental illness. These analyses were applied in order to identify any characteristics which distinguish specific sub-populations who are more likely to benefit from case management service, despite conflicting findings regarding its effectiveness for the aggregate population, as reported in the body of related research. However, in addition to a limited set of characteristics associated with benefit, the findings generated, a larger set of characteristics of patients likely to experience greater improvement without intervention. ^

Black/white disparities in infant mortality rates in the U.S.: A quality of care perspective

The infant mortality rate for non-Hispanic Black infants in the U.S. is 13.63 deaths per 1,000 live births while the IMR for non-Hispanic White persons in the U.S. is 5.76 deaths per 1,000 live births. Black women are 2 times as likely as White women to deliver preterm infants and Black women are 2 times as likely as White women to deliver low birth weight infants (weighing less than 2,500 grams at birth). Differential underlying risk factors among mothers of different racial/ethnic groups for delivering pre-term and low birth weight infants have been historically accepted as the cause of racial disparities in IMRs. However, differential underlying risk status may not be the only major causative factor. Differential or unequal access to and provision of care is widely speculated to be a leading contributing factor to the wide racial disparity in infant mortality.2 This paper conducts a systematic review of existing literature investigating racial disparities in obstetrical care provided by healthcare practitioners to evaluate whether inequities in healthcare services provided to pregnant mothers and their neonates exist. The search terms "racial disparities obstetrical care," "racial differences quality of prenatal care," and "infant mortality racial disparities" were entered into the EBSCO Medline, Ovid Medline, PubMed, and Academic Search Complete databases, and articles between years 1990–2011 were selected for abstract review. The only articles included were those that used statistical methods to assess whether racial inequalities were present in the obstetrical services provided to pregnant women. My literature search returned 5 articles. Four of the five studies yielded significant racial differences in obstetrical care. However, the one study that used a large, nationally representative valid sample did not represent significant differences. Thus, this review provides initial evidence for racial disparities in obstetrical care, but concludes that more studies are needed in this area. Not all of the studies reviewed were consistent in the use and measurement of services, and not all studies were significant. The policy and public health implications of possible racial disparities in obstetrical care include the need to develop standard of care protocols for ALL obstetrical patients across the United States to minimize and/or eliminate the inequities and differences in obstetrical services provided.^

UNDERSTANDING INTERRUPTIONS IN HEALTHCARE: DEVELOPING A MODEL

Developing a Model Interruption is a known human factor that contributes to errors and catastrophic events in healthcare as well as other high-risk industries. The landmark Institute of Medicine (IOM) report, To Err is Human, brought attention to the significance of preventable errors in medicine and suggested that interruptions could be a contributing factor. Previous studies of interruptions in healthcare did not offer a conceptual model by which to study interruptions. As a result of the serious consequences of interruptions investigated in other high-risk industries, there is a need to develop a model to describe, understand, explain, and predict interruptions and their consequences in healthcare. Therefore, the purpose of this study was to develop a model grounded in the literature and to use the model to describe and explain interruptions in healthcare. Specifically, this model would be used to describe and explain interruptions occurring in a Level One Trauma Center. A trauma center was chosen because this environment is characterized as intense, unpredictable, and interrupt-driven. The first step in developing the model began with a review of the literature which revealed that the concept interruption did not have a consistent definition in either the healthcare or non-healthcare literature. Walker and Avant’s method of concept analysis was used to clarify and define the concept. The analysis led to the identification of five defining attributes which include (1) a human experience, (2) an intrusion of a secondary, unplanned, and unexpected task, (3) discontinuity, (4) externally or internally initiated, and (5) situated within a context. However, before an interruption could commence, five conditions known as antecedents must occur. For an interruption to take place (1) an intent to interrupt is formed by the initiator, (2) a physical signal must pass a threshold test of detection by the recipient, (3) the sensory system of the recipient is stimulated to respond to the initiator, (4) an interruption task is presented to recipient, and (5) the interruption task is either accepted or rejected by v the recipient. An interruption was determined to be quantifiable by (1) the frequency of occurrence of an interruption, (2) the number of times the primary task has been suspended to perform an interrupting task, (3) the length of time the primary task has been suspended, and (4) the frequency of returning to the primary task or not returning to the primary task. As a result of the concept analysis, a definition of an interruption was derived from the literature. An interruption is defined as a break in the performance of a human activity initiated internal or external to the recipient and occurring within the context of a setting or location. This break results in the suspension of the initial task by initiating the performance of an unplanned task with the assumption that the initial task will be resumed. The definition is inclusive of all the defining attributes of an interruption. This is a standard definition that can be used by the healthcare industry. From the definition, a visual model of an interruption was developed. The model was used to describe and explain the interruptions recorded for an instrumental case study of physicians and registered nurses (RNs) working in a Level One Trauma Center. Five physicians were observed for a total of 29 hours, 31 minutes. Eight registered nurses were observed for a total of 40 hours 9 minutes. Observations were made on either the 0700–1500 or the 1500-2300 shift using the shadowing technique. Observations were recorded in the field note format. The field notes were analyzed by a hybrid method of categorizing activities and interruptions. The method was developed by using both a deductive a priori classification framework and by the inductive process utilizing line-byline coding and constant comparison as stated in Grounded Theory. The following categories were identified as relative to this study: Intended Recipient - the person to be interrupted Unintended Recipient - not the intended recipient of an interruption; i.e., receiving a phone call that was incorrectly dialed Indirect Recipient – the incidental recipient of an interruption; i.e., talking with another, thereby suspending the original activity Recipient Blocked – the intended recipient does not accept the interruption Recipient Delayed – the intended recipient postpones an interruption Self-interruption – a person, independent of another person, suspends one activity to perform another; i.e., while walking, stops abruptly and talks to another person Distraction – briefly disengaging from a task Organizational Design – the physical layout of the workspace that causes a disruption in workflow Artifacts Not Available – supplies and equipment that are not available in the workspace causing a disruption in workflow Initiator – a person who initiates an interruption Interruption by Organizational Design and Artifacts Not Available were identified as two new categories of interruption. These categories had not previously been cited in the literature. Analysis of the observations indicated that physicians were found to perform slightly fewer activities per hour when compared to RNs. This variance may be attributed to differing roles and responsibilities. Physicians were found to have more activities interrupted when compared to RNs. However, RNs experienced more interruptions per hour. Other people were determined to be the most commonly used medium through which to deliver an interruption. Additional mediums used to deliver an interruption vii included the telephone, pager, and one’s self. Both physicians and RNs were observed to resume an original interrupted activity more often than not. In most interruptions, both physicians and RNs performed only one or two interrupting activities before returning to the original interrupted activity. In conclusion the model was found to explain all interruptions observed during the study. However, the model will require an even more comprehensive study in order to establish its predictive value.

Use of Echogenic Immunoliposomes for Delivery of both Drug and Stem Cells for Inhibition of Atheroma Progression

Use of Echogenic Immunoliposomes for Delivery of both Drug and Stem Cells for Inhibition of Atheroma Progression By Ali K. Naji B.S. Advisor: Dr. Melvin E. Klegerman PhD Background and significance: Echogenic liposomes can be used as drug and cell delivery vehicles that reduce atheroma progression. Vascular endothelial growth factor (VEGF) is a signal protein that induces vasculogenesis and angiogenesis. VEGF functionally induces migration and proliferation of endothelial cells and increases intracellular vascular permeability. VEGF activates angiogenic transduction factors through VEGF tyrosine kinase domains in high-affinity receptors of endothelial cells. Bevacizumab is a humanized monoclonal antibody specific for VEGF-A which was developed as an anti-tumor agent. Often, anti-VEGF agents result in regression of existing microvessels, inhibiting tumor growth and possibly causing tumor shrinkage with time. During atheroma progression neovasculation in the arterial adventitia is mediated by VEGF. Therefore, bevacizumab may be effective in inhibiting atheroma progression. Stem cells show an ability to inhibit atheroma progression. We have previously demonstrated that monocyte derived CD-34+ stem cells that can be delivered to atheroma by bifunctional-ELIP ( BF-ELIP) targeted to Intercellular Adhesion Molecule-1 (ICAM-1) and CD-34. Adhesion molecules such as ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) are expressed by endothelial cells under inflammatory conditions. Ultrasound enhanced liposomal targeting provides a method for stem cell delivery into atheroma and encapsulated drug release. This project is designed to examine the ability of echogenic liposomes to deliver bevacizumab and stem cells to inhibit atheroma progression and neovasculation with and without ultrasound in vitro and optimize the ultrasound parameters for delivery of bevacizumab and stem cells to atheroma. V Hypotheses: Previous studies showed that endothelial cell VEGF expression may relate to atherosclerosis progression and atheroma formation in the cardiovascular system. Bevacizumab-loaded ELIP will inhibit endothelial cell VEGF expression in vitro. Bevacizumab activity can be enhanced by pulsed Doppler ultrasound treatment of BEV-ELIP. I will also test the hypothesis that the transwell culture system can serve as an in vitro model for study of US-enhanced targeted delivery of stem cells to atheroma. Monocyte preparations will serve as a source of CD34+ stem cells. Specific Aims: Induce VEGF expression using PKA and PKC activation factors to endothelial cell cultures and use western blot and ELISA techniques to detect the expressed VEGF.  Characterize the relationship between endothelial cell proliferation and VEGF expression to develop a specific EC culture based system to demonstrate BEV-ELIP activity as an anti-VEGF agent. Design a cell-based assay for in vitro assessment of ultrasound-enhanced bevacizumab release from echogenic liposomes.  Demonstrate ultrasound delivery enhancement of stem cells by applying different types of liposomes on transwell EC culture using fluorescently labeled monocytes and detect the effect on migration and attachment rate of these echogenic liposomes with and without ultrasound in vitro.

Renal Cryoablation: Investigation of Periprocedural Visualization Tools and Treatment Response Quantification

Cryoablation for small renal tumors has demonstrated sufficient clinical efficacy over the past decade as a non-surgical nephron-sparing approach for treating renal masses for patients who are not surgical candidates. Minimally invasive percutaneous cryoablations have been performed with image guidance from CT, ultrasound, and MRI. During the MRI-guided cryoablation procedure, the interventional radiologist visually compares the iceball size on monitoring images with respect to the original tumor on separate planning images. The comparisons made during the monitoring step are time consuming, inefficient and sometimes lack the precision needed for decision making, requiring the radiologist to make further changes later in the procedure. This study sought to mitigate uncertainty in these visual comparisons by quantifying tissue response to cryoablation and providing visualization of the response during the procedure. Based on retrospective analysis of MR-guided cryoablation patient data, registration and segmentation algorithms were investigated and implemented for periprocedural visualization to deliver iceball position/size with respect to planning images registered within 3.3mm with at least 70% overlap and a quantitative logit model was developed to relate perfusion deficit in renal parenchyma visualized in verification images as a result of iceball size visualized in monitoring images. Through retrospective study of 20 patient cases, the relationship between likelihood of perfusion loss in renal parenchyma and distance within iceball was quantified and iteratively fit to a logit curve. Using the parameters from the logit fit, the margin for 95% perfusion loss likelihood was found to be 4.28 mm within the iceball. The observed margin corresponds well with the clinically accepted margin of 3-5mm within the iceball. In order to display the iceball position and perfusion loss likelihood to the radiologist, algorithms were implemented to create a fast segmentation and registration module which executed in under 2 minutes, within the clinically-relevant 3 minute monitoring period. Using 16 patient cases, the average Hausdorff distance was reduced from 10.1mm to 3.21 mm with average DSC increased from 46.6% to 82.6% before and after registration.

Development of a SPECT -based three-dimensional treatment planner for radionuclide therapy with iodine -131

Accurate calculation of absorbed dose to target tumors and normal tissues in the body is an important requirement for establishing fundamental dose-response relationships for radioimmunotherapy. Two major obstacles have been the difficulty in obtaining an accurate patient-specific 3-D activity map in-vivo and calculating the resulting absorbed dose. This study investigated a methodology for 3-D internal dosimetry, which integrates the 3-D biodistribution of the radionuclide acquired from SPECT with a dose-point kernel convolution technique to provide the 3-D distribution of absorbed dose. Accurate SPECT images were reconstructed with appropriate methods for noise filtering, attenuation correction, and Compton scatter correction. The SPECT images were converted into activity maps using a calibration phantom. The activity map was convolved with an $\sp{131}$I dose-point kernel using a 3-D fast Fourier transform to yield a 3-D distribution of absorbed dose. The 3-D absorbed dose map was then processed to provide the absorbed dose distribution in regions of interest. This methodology can provide heterogeneous distributions of absorbed dose in volumes of any size and shape with nonuniform distributions of activity. Comparison of the activities quantitated by our SPECT methodology to true activities in an Alderson abdominal phantom (with spleen, liver, and spherical tumor) yielded errors of $-$16.3% to 4.4%. Volume quantitation errors ranged from $-$4.0 to 5.9% for volumes greater than 88 ml. The percentage differences of the average absorbed dose rates calculated by this methodology and the MIRD S-values were 9.1% for liver, 13.7% for spleen, and 0.9% for the tumor. Good agreement (percent differences were less than 8%) was found between the absorbed dose due to penetrating radiation calculated from this methodology and TLD measurement. More accurate estimates of the 3-D distribution of absorbed dose can be used as a guide in specifying the minimum activity to be administered to patients to deliver a prescribed absorbed dose to tumor without exceeding the toxicity limits of normal tissues. ^

Ascorbic acid effects on the immune system and type -1 /type -2 cytokine balance in humans

Vitamin C (ascorbic acid--AA) can have a substantial impact on human health by reducing the incidence and/or severity of coryza. Studies also suggest it has immunomodulatory functions in humans. Immune function is controlled by cytokines, such as type-1 cytokines (IFNγ) that promote antiviral immunity and type-2 cytokines (IL-4, IL-10) that promote humoral immunity. Knowing the mechanisms responsible for both antiviral immunity and type-1/type-2 cytokine balance, we sought to identify AA-induced alterations of human peripheral blood mononuclear cells (PBMC) in vivo and in vitro . We hypothesized that AA modulates the immune system, altering both number and function of PBMC. We first described the effect of 14 days of oral (1 gram) AA in healthy subjects. AA increased circulating natural killer (NK) cells, CD25+ and HLA-DR+ T cells, and PMA/ionomycin-stimulated intracellular IFNγ. We subsequently developed models for in vitro use. We determined that AA was toxic in vitro to T cells when used at doses found intracellularly but doses found in plasma from individuals taking 1gm/day AA were nontoxic. The model that most fully reproduced our in vivo intracellular cytokine findings used dehydroascorbic acid and buffers to deliver AA intracellularly. This model generated the largest increase in IFNγ at physiologic plasma concentrations. Previous studies demonstrate that chronic psychological stress is associated with a type-2 cytokine response. We hypothesized that vitamin C could prevent the type-2 cytokine shift associated with stress. In a study of medical students taking 1 g AA or placebo, a significant increase in IFNγ was seen intracellularly in CD4+ and CD8+ cells and in tetanus-stimulated cultures in the AA group only. We also observed increases in IFNγ/IL-4 and IFNγ/IL-10 ratios with AA supplementation, indicating a type-1 shift. Furthermore, we noted increased numbers of NK cells and activated T cells in the peripheral blood in the AA treated group only. Lastly, we investigated the role of the CD40L/CD40 and CD28/B7 costimulatory pathway in these cytokine alterations. AA did not have any effect on either pathway studied. Thus costimulatory pathways are not contributing to AA induced modulation of the type-1/type-2 immune balance. ^